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<p>Type 1 diabetes (T1D) risk has been associated with enteroviral infections, particularly coxsackieviruses B (CVB). Cellular host factors contributing to virus-induced islet autoimmunity remain unclear. We show that the Hippo pathway effector Yes-associated Protein (YAP) is markedly upregulated in the exocrine and endocrine pancreas of T1D and at-risk autoantibody-positive (AAb<sup>+</sup>) donors, along with its target CTGF. YAP expression correlates with CVB RNA presence, often in or near infected cells. YAP overexpression enhances CVB replication, islet inflammation, and β-cell apoptosis, whereas its inhibition halts viral replication in primary and immortalized pancreatic cells. In exocrine-islet co-cultures, CVB triggers YAP and target gene expression. In mice, chronic β-cell YAP expression impairs glucose tolerance, abolishes insulin secretion, and promotes β-cell dedifferentiation. Mechanistically, YAP, in complex with its transcription factor TEAD, induces its own negative regulator MST1. MST1 inhibition boosts viral replication and reduces β-cell apoptosis, constituting a negative feedback loop in which the reciprocal antagonism between YAP and MST1 balances viral replication and β-cell death during CVB infections. YAP is thus an important host factor for enteroviral amplification, offering a potential antiviral target in T1D.</p>

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The Hippo terminal effector YAP boosts enterovirus replication in type 1 diabetes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月6日

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  • Shirin Geravandi,
  • Huan Liu,
  • Heena Pahwa,
  • Murali Krishna Madduri,
  • Farah Atawneh,
  • Adib Miraki Feriz,
  • Sahar Rafizadeh,
  • Annabelle Elisabeth Kruf,
  • Mona Khazaei,
  • Pouria Bahrami,
  • David Gotti,
  • Mohamed Elawour,
  • Ruth M. Elgamal,
  • Ausilia Maria Grasso,
  • David Bund,
  • Blaz Lupse,
  • Zahra Azizi,
  • Omar Zabad,
  • Karim Bouzakri,
  • Marc Horwitz,
  • Alberto Pugliese,
  • Kathrin Maedler,
  • Amin Ardestani

摘要

Type 1 diabetes (T1D) risk has been associated with enteroviral infections, particularly coxsackieviruses B (CVB). Cellular host factors contributing to virus-induced islet autoimmunity remain unclear. We show that the Hippo pathway effector Yes-associated Protein (YAP) is markedly upregulated in the exocrine and endocrine pancreas of T1D and at-risk autoantibody-positive (AAb+) donors, along with its target CTGF. YAP expression correlates with CVB RNA presence, often in or near infected cells. YAP overexpression enhances CVB replication, islet inflammation, and β-cell apoptosis, whereas its inhibition halts viral replication in primary and immortalized pancreatic cells. In exocrine-islet co-cultures, CVB triggers YAP and target gene expression. In mice, chronic β-cell YAP expression impairs glucose tolerance, abolishes insulin secretion, and promotes β-cell dedifferentiation. Mechanistically, YAP, in complex with its transcription factor TEAD, induces its own negative regulator MST1. MST1 inhibition boosts viral replication and reduces β-cell apoptosis, constituting a negative feedback loop in which the reciprocal antagonism between YAP and MST1 balances viral replication and β-cell death during CVB infections. YAP is thus an important host factor for enteroviral amplification, offering a potential antiviral target in T1D.